EZH2 in lymphoid lineage specification and commitment

EZH2是多梳阻遏物复合物2的组蛋白甲基转移酶组分 （PRC2），其是抑制许多谱系特异性转录所需的 发展过程中的因素。最近的研究表明，无论是增益和损失的 EZH2的功能可能导致淋巴恶性肿瘤。在这里，我们将测试 假设EZH2是共同的淋巴祖细胞的承诺， 适应性淋巴细胞（B和T细胞）的命运，但不是先天性淋巴细胞（ILC1和ILC2） 命运我们将通过检查Ezh2失活的后果来检验这一假设。 在竞争性和非竞争性条件下通过流动的共同淋巴祖细胞 淋巴细胞的细胞计数分析，并通过使用体外测定， 分化的频率和对给定谱系的承诺。同时，我们将 通过检查EZH2靶基因表达的总体变化， EZH2缺陷引起的淋巴细胞及其祖细胞， 被EZH2结合并且不能经历H3K27三甲基化的基因， EZH2活性，在EZH2缺陷细胞中。总的来说，我们的研究将提供重要的 深入了解淋巴细胞谱系过程中控制基因表达的机制 规范和承诺。此外，我们将更好地了解如何 EZH2突变导致白血病和淋巴瘤以及如何治疗这些疾病 EZH2抑制剂可能会影响正常的淋巴细胞发育。

EZH2 is the histone methyltransferase component of the polycomb repressor complex 2 (PRC2), which is required for repression of numerous lineage specifying transcription factors during development. Recent studies have revealed that both gain and loss of function of EZH2 can contribute to lymphoid malignancy. Here we will test the hypothesis that EZH2 is required for commitment of common lymphoid progenitors to the adaptive lymphocyte (B and T cell) fates but not to innate lymphocyte (ILC1 and ILC2) fates. We will test this hypothesis by examining the consequences of Ezh2 inactivation in common lymphoid progenitors under competitive and non-competitive conditions by flow cytometric analysis of lymphoid cells and through the use of in vitro assays that measure both frequency of differentiation and commitment to a given lineage. In parallel we will identify EZH2 target genes by examining the global changes in gene expression in lymphocytes and their progenitors caused by EZH2-deficiency as well as identifying genes that are bound by EZH2 and fail to undergo H3K27 trimethylation, the hallmark of EZH2 activity, in EZH2-deficient cells. Taken together, our study will provide significant insight into the mechanisms controlling gene expression during lymphocyte lineage specification and commitment. In addition, we will gain a better understanding of how EZH2 mutations lead to leukemia and lymphoma and how treatment of these diseases with EZH2 inhibitors might influence normal lymphocyte development.